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Digestive
and
Liver
Disease
j o ur n a l ho me p a g e :w w w . e l s e v i e r . c o m / l o c a t e / d l d
Consensus
Treatment
of
Hepatitis
C
virus
infection
in
Italy:
A
consensus
report
from
an
expert
panel
Mauro
Viganò
A,∗,
Carlo
Federico
Perno
B,
Antonio
Craxì
C,
The
AdHoc
(Advancing
Hepatitis
C
for
the
Optimization
of
Cure)
Working
Party
AHepatologyUnit,OspedaleSanGiuseppe,UniversityofMilan,Milan,Italy
BVirologyUnit,DepartmentofExperimentalMedicineandSurgery,“TorVergata”UniversityofRome,Rome,Italy CDepartmentofGastroenterology,DiBiMIS,UniversityofPalermo,Palermo,Italy
a
r
t
i
c
l
e
i
n
f
o
Articlehistory: Received8March2017 Accepted31March2017 Availableonline12April2017 Keywords:
Antiviraltreatment Cirrhosis
Direct-actingantiviralagents HepatitisC
RAS
Treatmentfailure
a
b
s
t
r
a
c
t
HepatitisCvirus(HCV)infectionremainsoneofthemaincausesofchronicliverdiseaseworldwide. Theadventofdirect-actingantivirals(DAAs)hassignificantlyimprovedthecourseofpatientswith chronicHCVinfection(CHC),duetotheabilityofthesedrugstoachievehighratesofsustainedvirological response(SVR).TheseexceedinglyhighratesofSVRandtheexcellentsafetydatahavebeenconfirmed inreallifepractice.Evolvingguidelineshavebeenissuedbynationalandinternationalscientific soci-etiesinaccordancewiththeprogressionofclinicalknowledgeandtheavailabilityofnewDAAs.These recommendations,however,maynotbeapplieduniversallybecauseofdelaysindrugsreimbursability indifferentcountriesandbecausesomeNationalHealthSystemsidentifyonlypatientswithadvanced diseaseasatreatmentpriority.ItalyinthisregardisaprototypeaboutDAAstreatmentofCHCpatients. WiththeaimtoassesstheItaliantreatmentexperiencewithDAAsandtorespondtounmetneedsin treatmentoptimizationofantiviraltherapyinspecificsettingsofCHCpatients,agroupofItalianexperts metinStresainFebruary2017.Thesummaryoftheconsiderationsarisingfromthistwo-daymeeting andsomestatementsregardingafewopenissuesarereportedinthispositionpaper.
©2017EditriceGastroenterologicaItalianaS.r.l.PublishedbyElsevierLtd.Allrightsreserved.
1. TheHCVtreatmentscenarioinItaly
HepatitisCvirus(HCV)infectionisoneofthemaincausesof chronicliverdiseaseworldwideandisresponsibleforalarge pro-portionofliver-relateddeaths,mostlybecauseofhepatocellular carcinoma(HCC)andcirrhosis[1,2].
Approximately 180 million people worldwide are currently infectedwithHCV,althoughreliableepidemiologicaldataare elu-sivebecauseoftheasymptomaticnatureoftheinfectionandthe
AlessioAghemoa,AlfredoAlbertib,PietroAndreonec,MassimoAndreonid,Stefano
Bonorae,MauriziaRossanaBrunettof,RaffaeleBrunog,SavinoBrunoh,Vincenza
Calvarusoi,NicolaCaporasoj,FrancescaCeccherini-Silbersteink, ValeriaCentok,
AlessiaCianciol,PieroColombattof,ElisabettaDegasperia,VitoDiMarcoi,Giovanni
DiPerrie,GianpieroD’offizim,StefanoFagiuolin,CarloFerrario,GiovanniBattista
Gaetap,AdrianoPellicelliq,SalvatorePettai,SaraPiovesanb,MassimoPuotir,
Gio-vanniRaimondos,FrancescoPaoloRussot,GloriaTalianiu,UgoTramav,EricaVillaw,
AnnaLindaZignegox a-xSeeAppendixA.
∗ Correspondingauthorat:HepatologyUnit,OspedaleSanGiuseppe,University ofMilan,ViaS.Vittore12,20123Milan,Italy.Fax:+39285994267.
E-mailaddress:mvigano72@gmail.com(M.Viganò).
lackofscreeningprogramsinmostcountries[3,4].EveninItalythe exactnumberofHCV-positivepatientsisunknown,howeveritis believedthatthereisalargeproportionofCHCpatients(roughly 1%), mostwithage>60years withadvanced liverdisease,with nearly80,000cirrhoticsandatleast3000withdecompensated dis-ease.Ontheotherhandareliableassessmentoftheimpactofthe infectionisrepresentedbythenumberofpatientstransplanted duetoHCV(500/year)andbydeathscausedbythevirus(about 10,000/year).
UntiltheendofFebruary2017,68,270HCVpatientshadbeen treated with DAAs (http://www.agenziafarmaco.gov.it/content/ aggiornamento-epatite-c). According to the AIFA rules only patientswithmostadvanced liverdisease,curedHCC,listedfor livertransplant(LT),withHCVrecurrenceafterLTorafter trans-plantofsolidorganotherthanliver,andwithsevereHCV-related extra-hepaticmanifestations(EHMs)couldbeconsideredforthe DAAs treatment. The treated patients were: 43,453 (64%) cir-rhoticswithorwithoutHCC(curedwithsurgicalorloco-regional therapies); 18,497(27%) METAVIRfibrosis score F3;3191 (4%) with severe EHMs, i.e. cryoglobulinemic syndrome with organ damageorB-celllymphoproliferativesyndromes;1908(3%)with post-LT recurrence, 620 (1%) METAVIR F0-F2 who underwent http://dx.doi.org/10.1016/j.dld.2017.03.027
pegylatedinterferon(Peg-IFN)+Ribavirin(Rbv)+simeprevir(SIM) treatment;309(0,5%)listedforLTwithcirrhosisMELD<25and/or HCCwithintheMilancriteriawiththepossibilityofwaitingina listofatleast2monthsand292(0.5%)withCHCandnonliversolid organtransplantationorbonemarrowtransplantation.
BasedontheItalianNationalHealthSystemthereimbursability ofDAAswasthereforegrantedaccordingtourgencyoftreatment, withoutthepossibilitytousethese drugsin patientswithless advancedfibrosis(F0–F2).MoreoverthepriceofDAAswas negoti-atedcentrallywithprice/volumeagreementsandpay-per-patient reimbursement,regardlessoftreatmentdurationwithacostper patientofnearly6000–10,000euro.Thesemethodsof reimburse-menthaveallowedusingDAAslongerwithouttheneedtoidentify thepatientsbeingtreatedforshortertimetosavecosts.
2. ThenearfuturescenarioofHCVtreatment
AlthoughinItaly thetreatmentwasinitially reserved exclu-sivelytopatientswithadvancedliverdisease,inthelastmonths of2016thepercentageofF3patientsundergoingDAAsgradually increaseduptoreachingthenumberofF4patients,toindicate thattreatmentindicationismovingtowardlesserstagesof dis-ease.Recentlyithasbeenestimatedthatarestillpresentatleast 100,000–150,000F0–F3and10,000F4patientsthatneedantiviral treatment.Thesepatientsinthenextfouryearsmightallbetreated withanannualcostof400millioneuros.Theprogressivedecline ofpatientswithurgencyoftreatmentwillallowintheshortterm toexpandtreatmentcriteriawithout,however,bearthecurefor allinfectedpatients.Unfortunatelyourcountrylacksofaplanfor universalortargetedscreeningofinfectedpatients;aswellasofa strategyforretreatmentofpatientswhopreviouslyfailedDAAs, anda wideaccesstoDAAstreatmentfor peopleathighrisk of viraltransmission(i.e.womenofchildbearingagewho wishto becomepregnant;healthcare professional;peoplewithsexually transmitteddiseases;prisoners;peoplewhoinjectdrugs).
TreatmentofCHChasbeenrevolutionizedinthelastfewyears bytheintroductionofhighlyeffectiveandwelltoleratedDAAsable toachieve>90%ratesofSVRinmanygroupsofpatientsincluding thosewithmoreadvancedliverdisease.Successfulanti-HCV treat-mentcanstopliverdiseaseprogressioneventuallyreducingboth liver-relatedandoverallmortality[5,6].
The second wave of DAAs has significantly improved SVR rates,moreoverthesedrugsarebettertoleratedand havemore convenientonce-daily dosing regimens with shorter treatment schedules,i.e.12weeksinthemajorityofpatientsandinselected onesonly8weeks.
The future combination regimens withnew generation oral agentsmayfurtherincreaseSVRrateswithouttheneedforRbv, withshortertreatmentdurationsandwithmorefavorable toler-abilityprofiles.Withthesetreatmentswemightfinallyhavethe potentialtotreattheinfectionandnotjustthedisease,withthe aimtoeradicateHCVworldwide.
However,alsowiththese newDAAssometypes ofpatients willremain“difficulttotreat”,suchas:DAAs-experiencedpatients withresistanceassociatedvariants(RAVs);patientswith decom-pensatedcirrhosis,andgenotype3cirrhoticpatients.
During the last AASLD 2016 meeting, several new DAAs regimens were presented. The combination of sofosbuvir (SOF)/velpatasvir(VEL)withthenewpangenotypicHCVNS3/4A protease inhibitor (PI) Voxilaprevir (VOX) is one of the new a fixed-dose formulations. The POLARIS-2 study compared treat-mentwithSOF/VEL/VOXfor8weekstoSOF/VELfor12weeksin genotype1–6patientswithand withoutcompensatedcirrhosis whohavenotpreviouslyreceivedtreatmentwithDAAs.Patients with genotype 3 infection and cirrhosis were excluded from
thisstudy,butincludedinthePOLARIS-3study.Eightweeksof SOF/VEL/VOXachieved95%SVRratescomparedto98%withthe 12weekSOF/VELregimen.TheSVRrateswithSOF/VEL/VOXand SOF/VELwere91% vs99%and 96%vs98%in patientswithand withoutcirrhosis,respectively.Higherrelapserateswerereported inthe8weekstreatmentarmparticularlyingenotype1apatients [7].POLARIS-4studycompared 12 weeksof SOF/VEL/VOX with SOF/VEL in 182 and 151 patients, respectively, with previous failure of non-NS5A containing DAA regimens. SVR rates were higher among patientstreated withSOF/VEL/VOX compared to SOF/VEL(97%vs90%)[8].
In the randomized, open label, multicenter ENDURANCE-1 study, 703 naïve or treatment-experienced (prior IFN±Rbv or SOF+Rbv±IFN) genotype 1 patients without cirrhosis or with HIVco-infectionweretreatedforeither8or12weekswiththe combination of pangenotipic NS3/4A PI Glecaprevir (GLE) and pangenotipic NS5A inhibitor Pibrentasvir (PIB) [9]. Both arms showedhighratesofSVR:99%and100%,respectively.Thesame highSVRrate(99%)wasalsoreportedintheENDURANCE-4trial, that investigated the safety and efficacy of a 12-week GLE/PIB treatmentin121noncirrhoticpatientsinfectedwithHCV geno-type4-6,eithernaïveortreatment-experienced(priorIFN±Rbv orSOF+Rbv±IFN)[10],andalsointheENDURANCE-2trial,that investigatedthesafetyandefficacyofa12-weekGLE/PIB treat-mentin302naïveortreatment-experienced(priorIFN±Rbvor SOF+Rbv±IFN)noncirrhoticgenotype2patients[11].
TheSURVEYOR-II,Part3studyevaluatedtheefficacyandsafety ofGLE/PIBfor 12 or16 weeksin 131CHC patientsgenotype 3 withorwithoutcirrhosisincludingthosewithprior treatment-experience [12]. In experienced cirrhoticpatients, 16 weeks of GLE/PIBachieved96%ofSVRcomparedto98%ofnaïvepatients treatedfor12weeks,whereasintreatment-experiencednon cir-rhoticpatients, 16 weeks achieved96%of SVR vs 91%in those treatedfor12weeks.
The EXPEDITION-IV study reported 98% SVR rate in 104 genotype 1–6 patients with severe renal impairment (82% on hemodialysis) treated with12 weeks of GLE/PIB[13].This is a promisingstudy,sincetheDAAsrecommendedtodatefor treat-ment of HCV in patientswithadvanced renal insufficiencyare predominantlyactiveingenotypes1and4,whereasgenotypes2 and3patientswithend-stagerenaldiseasehavelittlechanceof treatment.
An interesting new fixed-dose triplet is the pangenotypic MK3combination,thatincludestheNS5Bpolymerasenucleotide inhibitoruprifosbuvir(formerlyMK-3682),thealready-registered NS3/4A PI Grazoprevir (GZR) and the next-generation NS5A inhibitorRuzasvir (RZR).The C-CRESTtrialevaluatedthesafety and efficacyof the MK3regimen, withor withoutRbv, in 664 genotype1–3patientswithandwithoutcirrhosis[14].Genotype1 patientswererandomizedto8or12weeksofthetriplet;genotype 2treatment-naïvepatientswererandomizedto8or12weeksof thetriplet,withorwithoutRbv,andcomparedwith16weeksof onlyMK3;genotype3treatment-naïveandexperiencedpatients wererandomizedto8vs12vs16weeks,withorwithoutRbv.MK3 for8or12weeksachieved93%vs98%SVRratesingenotype1a, and98%vs100%SVRrateingenotype1bpatients.Ingenotype2 treatment-naïvepatients,SVRrateswere86%,97%and100%inthe 8,12and16weeksarms,respectively.Ingenotype3,MK3regimen showed95%,97%and96%ofSVRinthe8,12or16weeksarmsof treatment.TheC-SURGEstudyevaluatedthesafetyandefficacyof theMK3regimeninpatientswhorelapsedafterLDV/SOForelbasvir (EBR)/GZRtreatment.Eightweeksaftertheendoftreatment,the SVRrateswere98%and100%inpatientsrandomizedtoreceive 16weeksMK3+Rbvor24weeksofMK3withoutRbv,respectively [15].
3. Treatmentofpatientswithgenotype2HCVinfection 3.1. Genotype2noncirrhoticandcompensatedcirrhoticpatients
According to current EASL Guidelines, genotype 2 patients should be treated with the combination of theNS5B inhibitor SOFplus theNS5Ainhibitor Daclatasvir(DCV)or VEL:the rec-ommendedtreatment scheduleis SOF+DCVor SOF/VEL for 12 weeksinnoncirrhoticandcompensatedcirrhoticpatients(Child PughscoreA),independentlyfromprevioustreatmenthistory[16]. AlthoughDCVisactiveagainstHCVgenotype2,literaturedata con-cerningSOF+DCVtreatmentingenotype2patientsarelimited: indeedSOF+DCVhasbeenevaluatedinaPhaseIIstudyin26 geno-type2naïvepatients,includingonly6(23%)patientswithcirrhosis. ThecombinationofSOF+DCV±Rbvfor24weeksresultedin24/26 (92%)patientsachievingSVR[17].ThefollowingPhaseIIIALLY-1 trialevaluatedSOF+DCVtreatmentinpatientswithadvanced cir-rhosis;includingasmallnumberofgenotype2infectedpatients: overall4outof5patients(80%)achievedSVR[18].Arecent sub-analysisof36genotype2patients,enrolledin5PhaseIIandIII clinicaltrialswithSOF+DCV-basedregimens,reported97%SVR rates,confirmingoptimalefficacyofthisregimeninsuchpatients, wherepresenceofbaselineRAVtoNS5Adidnotaffectthe achieve-mentofSVR[19].EfficacyofSOF+DCVcombinationingenotype2 patientshasbeenconfirmedalsobyreal-lifedata:asmallItalian studyin19genotype2patientsevaluatingSOF+DCVfor12or24 weeksreported100%SVRrates,where11outofthe19patientshad cirrhosisandhistoryofprevioustreatmentfailure,and5patients haddecompensatedcirrhosis[20].Recently,theRESIST-HCV(Rete SiciliaSelezioneTerapia-HCV)reportedhighrateofSVR(90%)in Child-Agenotype2cirrhoticpatientstreatedfor12 weekswith SOF+DCV[21].
Treatmentofgenotype2patientswithSOF/VELhasbeen eval-uatedin theASTRAL-1and 2trials,whererespectively 104/104 (100%) and 133/134 (99%) patientsachieved SVR following 12 weeksofSOF/VELfixeddosecombination.Patientpopulationin bothASTRALtrialsincludedapproximately15%of compensated cirrhoticpatients[22,23].LatestEASLtreatmentguidelinesdefine SOF+Rbv combination as suboptimal for genotype 2 patients. Thisstatement comesfrom real-lifereports showing SVR rates below 90%, especially in treatment experienced and cirrhotic patientsreceivingSOF+Rbvfor12weeks[24].Thesedatawere alsoconfirmedbya sub-analysisofgenotype2patientstreated in the TARGETstudy, where 49/62 (79%) and 20/24 (83%) cir-rhoticpatientsachievedSVRfollowinga12or16-weekcourseof SOF+Rbv,comparedwith201/221(91%)and13/14(93%)non cir-rhoticpatients,respectively.BaselineRbvdosewassignificantly associatedwiththeprobabilityofachievingSVR,whereoptimal chancesforSVRwerepredictedbybaselineRbvdose≥15mg/kg [25].InadditiontosuboptimalefficacyofSOF+Rbvinpatientswith advancedfibrosis,thepossibilitytoconsiderSOF+Rbvasa poten-tialoptionforselectedpatients(naïve, nocirrhosis),in orderto reducecostsderivingfrommultipleDAAsuse,hastobe discour-agedaswell,becauseindirecttreatmentcostswouldincreasedue tomanagementofRbv-relatedsideeffects.
3.2. Genotype2patientswithdecompensatedcirrhosis
Inpatientswithdecompensatedcirrhosis(ChildPughB/C),EASL guidelinesrecommendSOF+DCVorSOF/VEL+Rbvfor12weeks, howevertreatmentextensionto24weeksshouldbeconsidered.
TheASTRAL-4studycomparedSOF/VEL±Rbvfor12weeksvs SOF/VELfor24weeksinpatientswithdecompensatedcirrhosis: overall 12 genotype2 patientswereincluded inthestudy and 11achievedSVRexceptforonepatientwhodiedbecauseofliver failureonemonthafterstartingtreatment[26].
3.3. Retreatmentofgenotype2patientswithfailureto NS5A-containingregimens
Genotype2patientsfailingtoachieveSVRfollowingSOF+Rbv can be retreated with SOF+DCV+Rbv or SOF/VEL+Rbv for 12 weeks(noncirrhotic)or24weeks(advancedfibrosisF3/4).SOF/VEL combinationin33genotype2SOF-experiencedpatientsachieved 97%SVRrateinPOLARIS-4trial,wherecirrhosisaccountedfor46% ofpatientpopulation[8].Futureretreatmentoptionsincludethe SOF/VEL/VOXfixeddosecombinationthatachieved100%SVRin33 genotype2patientswithprevioustreatmentfailuretoSOF-based regimensinthePOLARIS-4study.
While waiting forfuture retreatmentoptions,viral sequenc-ing for confirmation of HCV genotype and RAV assessment is recommendedinordertoindividualizeandimproveretreatment strategy.Indeed,arecombinantHCV-2k/1bstraincarryingthe5 HCV-2and3HCV-1regionhasbeendescribedinliterature, espe-ciallyinEasternEurope[27]:thesepatientscouldbemisclassified asHCVgenotype2accordingtocommercialassaysforHCV geno-typeevaluatingthe5 UTRregion,and consequentlytheycould potentiallyhave beenundertreatedwithagenotype2 schedule notsuitableforgenotype1.AssessmentofHCVgenotypebyviral sequencing couldidentifytherecombinant strain and optimize retreatment option,although thisissuecouldalsobesolvedby upcomingavailabilityofpan-genotypicregimens.
Resistanceanalysisingenotype2patientsfailingtoachievethe SVR toNS5B-containing regimensfoundnoNS5B RAV develop-ment,asexpectedbythelowreplicativefitnessexhibitedbyviral strainscarrying amminoacidicchangesin theNS5B polymerase domain[28].Inaddition,presenceofNS5ARAVatbaselineseems nottoaffectefficacyofSOF+DCVregimeningenotype2patients, asdemonstratedbysubanalysisofDCVclinicaltrials[19].However, tilltheavailabilityofnextgenerationdrugs,Rbvadditionisstill rec-ommendedinordertooptimizeretreatmentresponserates,asRbv hasbeenshowntoimproveviralclearance,especiallyinpatients withadvancedfibrosisandbaselineRAVs.
3.4. Statements
• SOF+DCVorSOF/VELfor12weeksarethestandardofcare treat-mentforgenotype2F0–F4patients(ChildPughA).
• Ingenotype2patientswithdecompensatedcirrhosis(ChildPugh B/C),SOF+DCV±RbvorSOF/VEL±Rbvfor24weeksis recom-mended.
• SOF+Rbvhassuboptimalefficacyingenotype2cirrhoticpatients andisnotrecommendedaswellasintheotherpatientgroups duetoRbv-relatedsideeffects.
• Genotype2patientsfailingtoachievetheSVRusingSOF+Rbv regimenshouldberetreatedaccordingtoEASL recommenda-tions.ViralsequencingtoconfirmHCVgenotypeandRAVanalysis issuggestedtooptimizeretreatmentstrategies,whileRbv addi-tionisavalidoptiontillavailabilityofnext-generationdrugs. 4. Treatmentofpatientswithgenotype3HCVinfection
Current treatmentrecommendations in genotype 3 infected patientsdifferaccordingtoliverfibrosisstageandprevious treat-mentexperience.
4.1. Genotype3patientswithoutcirrhosis
According to American (AASLD) Guidelines, all genotype 3 patientswithout cirrhosis shouldbe treated withSOF+DCVor SOF/VELfor12weeks,whileEASLGuidelinesrecommendRbv addi-tioningenotype3noncirrhoticpatientswithprevioustreatment
failuretoPeg-IFN+RbvtherapyandbaselineNS5ARASY93H(if resistancetestingavailable)[16,29].
IntheALLY-3trial,73/75(97%)naïveand32/34(94%) treat-mentexperiencednoncirrhoticpatientsachievedSVRfollowing SOF+DCVadministrationfor12weeks[30].AdditionofRbvis rec-ommended,asSVRdecreasedto50%inpatientswithbaselineY93H [31].
EfficacyofSOF/VELcombinationingenotype3patientshasbeen investigatedintheASTRAL-3trial,where160/163(98%)naiveand 31/34(91%)experiencedpatientswithoutcirrhosisachievedSVR following 12 weeksof SOF/VELtreatment.SVR rate inpatients withnoNS5ARAVatbaselinewas97%(225/231)vs88%(38/43) inpatientswithbaselineNS5A RAVs(16%prevalence)and 84% (21/25)inpatientswithbaselineY93H[23].Eighty-ninegenotype 3patientsreceivedSOF/VELcombinationfor12weeksalsointhe POLARIS-2trial,resultingin86patients(97%)achievingSVR[7]. 4.2. Genotype3patientswithcirrhosis
Inpatientswithcirrhosis,EuropeanandAmericanGuidelines recommendSOF+DCV+Rbvfor24weeksorSOF/VEL+Rbvfor12 weeks independently from previoustreatment experience.Rbv shouldbeaddedtoSOF/VELinpresenceofbaselineNS5ARAVY93H, whiletreatmentshouldbeextendedto24weeksifRbvcannotbe administered[16,29].
TheSOF+DCV+Rbv24-weekcoursewasrecommendedbasing onexpertopinions,asnodatahasbeengeneratedyetbyclinical tri-alsincirrhoticpatientswiththistreatmentschedule.IndeedPhase IIItrialsinvestigated only 12 or 16 week-coursesof SOF+DCV. TheALLY-3trialdemonstratedsuboptimalefficacyofSOF+DCV for12weeksincirrhoticpatients,asonly11/19(58%)naiveand 9/13(69%)experiencedpatientsachievedSVR,wherehighrelapse ratewasprobablyrelatedtothestudydesign,notincludingRbv administration[30].AdditionofRbvandtreatmentextensionto16 weeksexploredbytheALLY-3+trialresultedin21/24(88%)and 24/26(92%)patientsachievingSVRfollowing12or16weeksof SOF+DCV,wherePeg-IFN-experiencedpatientsaccountedforthe majorityofpatientpopulation[32].Despitetheabsenceof clin-icaltrialdata,efficacyofSOF+DCV+Rbvfor24weekshasbeen confirmedinreal-lifesettings.TheRESIST-HCVreported91%SVR rateinChild-Agenotype3cirrhoticpatientstreatedfor24weeks withSOF+DCV+Rbvbutonly84%in thosetreatedwithoutRbv [21].TheLombardiaHepatitisNetworkreportedoverall97%SVR ingenotype3patientswithadvancedfibrosis(F3/4)[33]. Excel-lentresultwerealsoreportedbytheCLEO,showing98%and96% SVRratesinpatientstreatedwith24weeksofSOF+DCV+Rbvflat dose(800mg)orSOF+DCV-weight-basedRbvdose,respectively [34].TheFrenchcompassionateuseprogramingenotype3cirrhotic patientstreatedwith24weeksofSOF+DCVreported86%SVRrate inpatientswithanydegreeofcirrhosiswithoutSVRincreasein thosewhoreceivedadditionalRbv(82%)[35].
In the ASTRAL-3 trial, 40/43 (93%) naive and 33/37 (89%) experiencedgenotype3patientswithcirrhosisachievedSVR fol-lowing SOF/VELfor 12 weeks [23]. In the POLARIS-3trial,109 genotype3cirrhoticpatients,including32(29%)withprevious Peg-IFN+Rbvtreatmentfailure,receivedSOF/VELfor12weekswith98% (105/109)SVRrate[36].
4.3. Genotype3patientswithdecompensatedcirrhosis
Patients with decompensated cirrhosis should receive SOF+DCV+Rbv for 24 weeks or SOF/VEL combination for 24 weeksaccordingtoEASLguidelines[16].
In a largeEuropean compassionate use program the use of 24weeksofSOF+DCV±RbvinChildB/CCHCpatients,reported
79%(19/24)and 88%(15/17) SVRratesin patientstreated with SOF+DCVandSOF+DCV+Rbv,respetively[37].
TheASTRAL-4trial,comparingSOF/VELwithorwithoutRbvfor 12weeksvsSOF/VELfor24weeksin36genotype3decompensated patients,showedthebestSVRratesinthe12-weekSOF/VEL+Rbv arm:11/13(85%)patientsachievedSVRcomparedto7/14(50%) and6/12(50%)patientsintheSOF/VEL12 and24weekcourse, respectively[26].
4.4. FuturetreatmentoptionsfornaiveandPeg-IFNexperienced genotype3patients
AllupcomingsecondgenerationDAAcombinationsareeffective ingenotype 3patientsandhavealready providedvery promis-ingresults:theGLE/PIBcombinationwasevaluatedingenotype 3naivenoncirrhoticpatientswithashortened8-weektreatment courseintheSURVEYOR-II(Part2)andENDURANCE-3trials,where 28/29 (97%) and 149/157(95%) patients achieved SVR, respec-tively[38,39].TheSURVEYOR-II(Part3)investigatedtheefficacyof GLE/PIBfor12or16weeksin131genotype3patientswithprevious treatmentexperience(19%failingSOF+Rbvcombination)and/or cirrhosis,providingSVRratesexceeding90%acrossalltreatment arms[12].AsGLE/PIBcombinationshowsnorenalmetabolism,it representsapromisingtreatmentoptionforgenotype3patients withadvanced chronickidneydisease,whocurrentlycannotbe treatedwithSOF-basedcombinations.
TheMK3triplecombinationwasevaluatedintheC-CREST pro-gram,where337genotype3patientsreceivedMK3±Rbvfor8, 12or16 weeks.SVR rateswere95%inthe8-weekarm,where 74/103(72%)patientsweretreatment-naiveandonlynoncirrhotic patientswereincluded.Inthe12-weekarm,155/159(97%)patients achievedSVR,thisarmincludingalsopatientswithcirrhosisand 58(36%)Peg-IFN+Rbvexperiencedpatients.Inthe16-weekarm, 72/75(96%)achievedSVR,wherethemajorityofpatients(61/75, 81%)weretreatmentexperienced.OverallSVRratesintreatment experiencedpatientswithcirrhosisexceeded96%bothinthe12 and16-weekduration,independentlyfromRbvaddition[14].The shortened8-weektreatmentdurationin patientswithcirrhosis hasbeenevaluatedforthefirsttimewiththetripleSOF/VEL/VOX pan-genotypiccombination,wherethePOLARIS-3trialshowed96% SVRratein110genotype3patients,including35(32%) Peg-IFN-experiencedpatients[36].
4.5. Retreatmentofgenotype3patientswithfailureto NS5A-containingregimens
VirologicfailuretoaNS5A-containingregimen,i.e.DCVin geno-type 3 patients, results in selection of NS5A RAV, which show highreplicativefitnesscomparedtowild-typevirusand conse-quently persistlong-term,exhibiting also cross-resistance with otherNS5Ainhibitors.Retreatmentoptionsforgenotype3patients failingSOF+DCVshouldbebasedonaDAAcombinationregimen includingallthreeNS3,NS5AandNS5Binhibitors.ThePOLARIS-1 trialshowedverypromisingresultofSOF/VEL/VOXcombination ingenotype 3 NS5A-experiencedpatients: 74/78(95%) patients achievedSVR,whilebaselinepresenceofNS5ARAVdidnotaffect treatmentefficacy[40].
4.6. Statements
• Genotype3patientswithoutcirrhosisshouldreceiveSOF+DCV orSOF/VELfor12weeksiftreatmentnaive,whileRbvshouldbe addedinPeg-IFNexperiencedpatientsinpresenceofbaseline NS5ARAVY93H.
• Genotype 3 patients with compensated cirrhosis should be treatedwithSOF+DCV+Rbvfor24weeksorSOF/VEL+Rbv(if baselineNS5ARAVY93Hispresentordocumented)for12weeks. • In genotype 3 patients with decompensated cirrhosis, SOF/VEL+RbvorSOF+DCV+Rbvfor24weeksarerecommended. • Retreatment of genotype-3 infected patients who previously failedarecommended24-weeksSOF+DCV+Rbvregimenwith Y93H RAV should not be considered for retreatment with SOF+VEL+Rbvfor24weeks,butratherwaitfornew combina-tion,whetherretreatmentcanbedelayed.
5. RetreatmentofpatientsfailingtoachieveSVRwith DAA-basedregimens(DAA-failures)
UntiltheendofFebruary2017,68,270patientshavealready beentreatedwithIFN-freeDAA-combinationsinItaly.Accordingto currentliterature,suggestinganaverageof2–3%virologicfailures tocurrentDAAregimens,approximately2000–4000DAA-failure patientsarewaitingforefficientretreatmentoptions.
Three types of virologic failures exist, most common being relapse,thatisposttreatmentviremiareappearancefollowingHCV RNAundetectabilityattheendoftherapy.Nonresponse,definedas HCV-RNA>1000IU/mLatweek4oftreatment,andbreakthrough definedason-treatmentdetectableviremiaintwocontrolsafter HCV RNA undetectability. Non response and breakthrough are rarelyobservedwithDAAtreatment,andtheiroccurrenceshould raise questions on patient’s adherence and/or on wrong HCV-genotypeassignment.
DAA-failurecan resultfrom multiplefactors, which needto becarefullyevaluatedwhenconsideringpossiblereasonsfornot achievingtheSVRonacase-by-casebasis.Indeed,treatment out-comecanbeaffectedbypatient-relatedfactorssuchascompliance andunknowndrug-to-druginteractions(DDI)potentiallyreducing DAAefficacy(includingover-the-counter,recreationaldrugsand herbalsupplements).However,DAA-failureisoftentheresultofa suboptimaltreatmentregimen,definedby(co)presenceofmultiple unfavorablefactors.TheseincludesuboptimalDAAcombinations use(lowpotencyorlowbarriertoresistance),tooshorttreatment duration,useofRbv-freeregimenswhethertreatmentschedule couldhaverequiredRbvaddition,previoustreatmentexperience, baselineHCVRNAviralloadandbaselineRAVs.
Allthesebaselinefactorsneedtoberetrospectivelyevaluated whenconsideringreasonsfor treatmentfailure, (seenext para-graph).
Accordingtorecentdata,upto4%ofDAA-failuresarecaused bywrongbaselineHCVgenotypedetermination,especiallywhen HCVgenotype wasassessed at thebeginning ofpatient’s clini-calhistoryusingold-generationteststhatcarriedincreasedrisk of genotype/subtype misclassification [41]. Viral sequencing is thusrecommendedattreatmentfailureinordertoconfirmHCV genotype,especiallywhenbreakthourghornon-responsestoDAA treatmentareobserved.Inaddition,duetofrequentdevelopment ofRAVsatfailureandtheircriticalroleinretreatment optimiza-tion,resistancetestinginallthreeresistance-relevantNS3,NS5A, NS5Bregionshasalwaystobeperformed.
5.1. RAVatvirologicalfailureandretreatmentoptions
Failure to DAA-based regimens invariably results in RAVs selection,asdrugpressuremodifiesviralpopulation,thatis pro-gressively enriched in resistant strains. At virologic failure, all patientscarryRAVstoatleastoneDAAtheyhavebeenexposed to:RAVsanalysisof 261patientsfailinga DAA-basedregimens inamulticentreItalianstudyfound72%NS3and93%NS5A-RAVs prevalenceinpatientsfailingaNS3andNS5A-containingregimen,
respectively, whileonly19.7%–31%of NS5B-RAVweredetected after NS5B-containing regimens [42]. These figures are consis-tentwithdifferentreplicativefitnessexhibitedbyRAVtypes,and resultinheterogeneousclinicalrelevanceofRAVswhen consider-ingretreatment.
Indeed,aminoacidicsubstitutionsinNS5Bregionresultinviral strains withextremely low replicative fitness, due to the high conservationofRNApolymerasecatalyticsite.Asaconsequence, retreatmentofSOF-failedpatientswithSOF-containingregimens yieldsoptimalefficacy[43].
AlsoNS3RAVsdisplay lowerreplicativefitnesscompared to wild-typevirus,sothatresistantstrainsareprogressivelyreplaced bywild-typeonesfollowingtheendoftreatment.Ithasbeen esti-matedthatapproximately10–12monthsafterPI-discontinuation, theentireviralpopulationwouldhavebeenrevertedtowild-type, althoughoutcomeofNS3-basedretreatmentintermsofpossible NS3-RAVre-emergencehasnotyetbeendefined[44].
AccordingtoEASL Guidelines,theoptimalretreatment regi-menforpatientsfailingafirstDAAcourseshouldcontainoneDAA withhighbarriertoresistance(i.e.NS5Bnucleotideinhibitors)plus 1–3otherDAAs,withnocross-resistancewiththeDAAsalready administered.Rbvshouldbeaddedinallretreatments.A12-week course is recommended in patientswith mild fibrosis (F0–F2), wherepatientswithadvancedfibrosis(F3/4)shouldberetreated for24weeks[16].Asaconsequence,NS3-RAVcarriersare“easyto retreat”patients,astheycanefficientlyberetreatedwithcurrently availableSOFplusNS5Acombinations[45].
Ontheotherhand,NS5ARAVdisplaysthesamereplicative fit-nessaswild-typevirusandpersistlong-term,remainingdetectable morethantwoyearaftertreatmentfailure.NS5Ainhibitorshave similarresistanceprofiles,withconsequentriskofcross-resistance afterfailure[46–48].AccordingtotheprincipleofDAAclassswitch, thesepatientscouldberetreatedonlywithaNS3-containing reg-imens, such as SOF+SMV+Rbv. However, this regimen is not recommendedindecompensatedcirrhosisandcouldresultin sub-optimalantiviralefficacyingenotype1apatientsduetolowSMV resistancebarrier.
The most difficult therapeutic scenario is in the manage-ment of patients harboring RAVs to multiple DAA classes, for example NS5A plus NS3: these patients could be retreated only with multiple DAA combinations targeting all replication steps, such as a NS5B nucleotide polymerase inhibitor±NS5B non-nucleotide+NS5A+NS3inhibitor.For example,retreatment strategies for genotype 1 patientscouldinclude SOF+GZR/EBR, SOF+3D combination, SOF+SMV+DCV, however these combi-nations are out of reimbursability policies in many countries. “Unconventional” approaches out of drug labels/market reim-bursementneedcooperationfromdrugcompaniesandrefiningof nationalreimbursementrulestobetranslatedinclinicalpractice. AccordingtoEASLguidelines,retreatmentofgenotype3patients failing SOF+DCVcombination couldbe basedonSOF/VEL+Rbv for24weeks,howeverinpresenceofY93HRAVatfailurethese patientsshouldnotbeconsideredforretreatmentatthepresent time,butratherwaitforfutureoptions.
Next-generationDAAcombinationcouldsolvetheunmetneed for efficientretreatmentoptions:indeed inthePOLARIS-1trial, SOF/VEL/VOX combination achieved 96% SVR rates in 263HCV genotype1–6NS5A-experiencedpatients,andSVRrateswerenot affectedbybaselinepresenceofmultipleRAVs(NS5AandNS3)[40]. AlsotheMK3combinationdemonstratedoptimalefficacyin geno-type1patientswithpreviousDAAfailure.IntheC-SURGEstudy, comparingMK3+Rbvfor 16 weeksvs MK3for24 weeksin 94 genotype1patientsfailingSOF/LDVorGRZ/EBR,SVRrateswere above98%independentlyfrombaselineRAVprofileandtreatment scheduleadministered[15].Finally,theMAGELLAN-1study,that investigatedtheuseofGLE/PIB±Rbvin50DAA-experienced
geno-type1patients,achieved100%SVRindependentlyfrombaseline NS5AorNS3RAVs[49].
As a consequence, if not clinically urgent, retreatment of patientswithmultipleRAVstoNS5AandNS3couldbedeferred, waitingforupcomingnewtreatmentoptions.
5.2. Statements
• Resistancetesting aftertreatment failurein all3 genes (NS3, NS5A,NS5B[forthetwodifferentclassesofnucleosideand non-nucleosideinhibitors]independentlyfromthefailureregimen) ismandatoryinordertooptimizeretreatmentstrategy.1 • HCVsequencingcanbebasedonSangerpopulationmethodor
byultra-deep sequencingusinga cut-offof15%prevalence.It canconfirmthepreviousgenotypeandsubtypeassignment,but canalsoattributeadifferentHCV-genotypehighlightingcases ofpreviouswronggenotypeassignationbycommercialassaysor occurrenceofpotentialre-infectioninsteadofvirologicalrelapse, avoidingtheninappropriateretreatmentregimens.
• Resistancetestingshouldbeperformedassoonaspossibleafter documentationoffailure,providedthatHCVRNAhasreacheda valueofatleast1000IU/mL,accordingtothethresholdlimitsfor virologylaboratoriesforHCVsequencing.
• Clinicalandvirologicalinformationrequiredforresistancetest performanceandinterpretationshouldbeprovidedcontextually withbloodsamples.
• Accordingtoresistanceresults,currentre-treatmentstrategies forpatientsfailingafirstcoursewithDAAsshouldincludeatleast 2activedrugclasses,withapreferentialuseofonedrugwith highgeneticbarriertoresistance,andwithextendedtreatment durationsandadditionofRbv,otherwisewaitingforbetterfuture optionsisrecommended.
• If a deferred treatment has been considered, and in case of presence of RAV at failure,in order toassist the therapeutic choicewhenstartingare-treatment,HCVsequencingshouldbe repeated(onlyinthegenewithpreviousRAV)andshouldbe basedondeepsequencing.
• Retreatmentofgenotype3patientswhopreviouslyfaileda rec-ommended24-weeksSOF+DCV+RbvregimenwithY93HRAV shouldnotbeconsideredforretreatmentwithSOF/VEL+Rbvfor 24weeks,butratherwaitfornewcombinations,ifretreatment canbedelayed.
6. BaselinefeaturesinfluencingHCVtreatmentchoice Whenevaluatingtreatmentoptions,choiceofthebest treat-mentregimenandscheduleattheindividuallevelshouldconsider manybaselinefactors,suchasHCVgenotype,viralload,liver fibro-sisstageandprevioustreatmentexperience,baselineRAV,DDIand patientcomorbidities.Carefulevaluationofthesebaselinefeatures canhelptooptimizetreatmentstrategyandmaximizeitsefficacy. 6.1. HCVgenotype
SomeDAA-basedregimensarestillgenotype/subtype depen-dent,sothatapreciseassessmentofHCVgenotypeandsubtype ismandatoryinordertoavoidmistreatingduringthefirstDAA course.Inmanypatients, HCVgenotypeand subtypehavebeen determinedatthebeginningofclinicalhistory,oftenusing
old-1 Note:Itwouldbedesirabletopreserveasamplebeforestartingtreatmentwith
DAA,becauseincaseoffailureandpresenceofRAV,thestudyofthebaselinesample mayhelptodistinguishiftheresistanceoccurredontreatmentfailureorifitwas alreadypresentasnaturalresistancebeforetreatment.Thisinformationmayhelp tosettothebestthenextregimen.
generationtests,i.e.thecommercialassayINNO-LIPAversion1.0; thesetests carriedan increasedrisk of misclassifyinggenotype 1a subtype, that nowadays requires addition of Rbv or treat-mentextensionin manyDAA regimens.Thecurrentlyavailable second-generationcommercialassaysforHCVgenotypeshowgood concordance(around90%)withgenotypeassessmentperformed byHCVsequencingintheNS5B,orNS3,orNS5Aregion[50],and arenowconsideredthestandardofcareforHCVgenotyping,so thatHCVsequencingisnotroutinelyrecommended.However,HCV sequencingcanbeusefulinthoserarecaseswheregenotypecannot bedeterminedbythecommercialassays(suchascasesofmixed infection,orindeterminate,orgenotype1withoutsubtype infor-mation).
6.2. HCVRNAviralload
Whenchoosingtreatmentregimen,viralloadshouldbe consid-eredinsomeselectedcases,whereHCVRNAlevelsdrivetreatment durationorneedforRbvaddition.ThisisthecaseforSOF/LDV treat-mentinnaivegenotype1patientswithoutcirrhosis,whocanbe treatedwithashortened8-weekcourseofSOF/LDVifHCVRNAis <6,000,000IU/mL,accordingtoasub-analysisofION-3trial[51]. Ingenotype4Peg-IFN-experiencedpatientsandinallgenotype1a patientswithHCVRNA>800,000IU/mL,treatmentdurationwith GZR/EBRcombinationshouldbeextendedfrom12to16weeks withRbvaddition,asapooledanalysisofPhaseIIandPhaseIII GZR/EBRtrialsshowedsuboptimalratesinpatientswithHCVRNA >800,000IU/mLandbaselineRAVtoEBRreceivingGZR/EBRfor12 weekswithoutRbv[52,53].Thesedatageneratedthedruglabel recommendations,wherebaselineRAVsequencing,ifavailableor baselineHCVRNAleadchoiceoftreatmentdurationandneedfor Rbvuse.
6.3. Liverfibrosisstage
Liver disease assessment is mandatory in order tooptimize treatmentstrategy: intensified treatmentcourses (extensionto 24 weeks and/or Rbv addition) are required with most DAA combinationsinpresenceofcirrhosis.Moreover,NS3-containing regimensarenotrecommendedin decompensatedChildBorC patients(3D/2D,SMVandGRZ/EBR),asliverimpairmentresults inincreasedexposuretoNS3inhibitorconcentrationsand, conse-quently,enhancedriskofadverseevents.
Liverstaging can beassessedbynon-invasive methods (like TransientElastography)and,incirrhoticpatients,detailed medi-calhistoryconcerningpreviousepisodesofliverdecompensation shouldberecorded,togetherwithbaselineChildPughscore assess-ment,inordertodefinethepotentialriskofdecompensationand livertoxicity.
6.4. Previoustreatmentexperience
EASLGuidelinesrecommenddifferenttreatmentregimensin naivevsPeg-IFNexperiencedpatientswithmanyDAA combina-tions,suggestingRbvadditionortreatmentextension[16].This is the case for SOF/LDV combination, where genotype 1a, 4–6 experienced patientsshould betreated withRbvaddition. The sameconceptistrueforgenotype3patientsreceivingSOF/VELor SOF+DCVtreatment,whereexperiencedpatientsbenefitfromRbv use,especiallyinpresenceofbaselineY93HRAV.Whenconsidering GZR/EBRcombination,treatmentextensionto16weeksandRbv additionisrecommendedingenotype1atreatmentexperienced patientswithbaselineviralload>800,000IU/mL.
6.5. BaselineRAV
Duetothelackofproof-readingactivityoftheHCVRNA poly-meraseand thehighHCVreplicationrate,RAVsnaturallyoccur andpreexistDAAexposure,beingdetectedwithdifferent preva-lence accordingtothe sequencingtechnique (population-based sequencingvs deepsequencing). Potential role ofbaseline RAV indeterminingtreatmentoutcomehasbeenwidelydiscussed:a sub-analysisoftheSOF/LDVphaseIIandIIIclinicaltrialsshowed thatbaselineNS5ALDV-specificRAVnegativelyaffectedtreatment outcomeinsomepatientsubsets,suchasgenotype1a treatment-experiencedpatients.BaselineLDV-RAVweredetectedin8–16% ofpatientsusinga15%viralsequencingcutoff[54].Ontheother hand,anotherstudydemonstratedthatbaselineRAVhadonly min-imaleffectingenotype1apatientsreceivingSOF/LDVcombination, andRAVcouldbeovercomebytreatmentextensionorRbv addi-tion[55].EASLguidelinesrecommendRbvadditioningenotype 1aexperiencedpatientswithSOF/LDVorSOF+DCVregimensin presenceofbaselineRAVthatconferhigh-levelresistancetoNS5A inhibitors,howeverRAStestingisnotmandatoryifnotavailable.
AnothertreatmentchoiceinfluencedbybaselineRAVis treat-mentdurationofGZR/EBRcombinationtherapy,whereSVRrates inpatientstreatedfor12weekswithoutRbvdroppedto52%and 29%innaiveandexperiencedgenotype1apatients,respectively. ThesedataleddruglabeltorecommendRAVsequencingat base-lineinordertoextendtreatmentdurationto16weeksandaddRbv inpatientsharboringRAVtoEBR.IfRAVtestingisnotavailable,a baselineviralload>800,000IU/mListhesurrogatecut-offtodrive treatmentintensification[16].
Finally,additionofRbvhasbeenrecommendedintreatment experiencedgenotype3patientsreceivingSOF+DCVorSOF/VEL combinationinpresenceofbaselineRAVY93H,resultingin subop-timalSVRratesinALLY-3andASTRAL-3trials[31,36].
6.6. Drug–druginteractions(DDIs)
Carefulevaluationofpatient’sco-medications(including over-the-counter,herbalsandsupplements)ismandatorywhen choos-ingtheappropriatetreatmentregimen,inordertoavoidsignificant DDIsresultinginreducedtreatmentefficacyorriskforsignificant sideeffects.OneofthemostrelevantDDIsisbetweenSOFand amio-darone,whoseco-administrationiscontraindicatedduetoriskof severebradycardia.Whilethepathogenicmechanismhasnotbeen completelyelucidatedyet,thiscontraindicationhasbeenextended toallSOF-containingregimensand,duetoamiodarone accumu-lation, a wash-out period of minimum three months hasbeen recommended prior to SOF-based treatments. Other significant DDIsresultingincontraindicatedco-administrationincludestatins with3Dregimen(rosuvastatinwithSOF/LDV),andcyclosporine withGRZ/EBR,duetotoxicityriskresultingfromincreasedGZR concentrations.Finally,manyanticonvulsantdrugslike phenobar-bitaland carbamazepinecannotbeco-administered withmany DAAsbecausetheydecreaseantiviraltreatmentefficacy.
Most common drug classes involved in DDIs with DAA-based regimens are cardiovascular (antihypertensive, antiar-rhythmic agents), antipsychotic and immunosuppressive drugs (tacrolimus, cyclosporine, mycophenolate), some anti-platelets andanti-fibrinolyticagents.First-generationDAAs,especiallyNS3 inhibitors, are characterized by more DDIs compared to NS5A inhibitors, due to the metabolic pathway involving cytocrome CYP3A4,which iscommontomany otherdrugs.Whilein some casesmedicationchangeis requiredduringantiviral treatment, moreoftenonlya carefulmonitoringforsideeffects isneeded. Second-generation drugs represent a significant improvement in DDI profile,resulting in easier management of patient’s co-medications.
6.7. Co-morbidities
Patient’s comorbidities(including HIV and HBV co-infection, cardiovascularandrenaldiseases,cryoglobulinemiaand haema-tologicdiseases)playanimportantroleintreatmenteligibilityand DAA-combinationdecision.Somecomorbiditiesconferurgency cri-teriaforantiviraltreatmentindependentlyfromliverdiseasestage, i.e.EHMssuchasHCV-relatedcryoglobulinemiaandnon-Hodgkin lymphoma. While HIV-infected patientsare now consideredas mono-infectedpatientsaccordingtotreatmentefficacy,choiceof treatmentcourseisstronglyinfluencedbyDDIswith antiretrovi-raltherapy.PatientswithconcurrentHBVinfectionrequirecareful monitoringand/orHBVtreatmentinordertopreventHBV reacti-vationduringanti-HCVtherapy.
Mostrelevantco-morbiditiesaffectingtreatmentdecisionare cardiovascularandrenaldiseases.Inthefirstcase,DDIswith car-diovascularagentshavetobecarefullyevaluatedandcanresult incontraindicated antiviraltreatment(i.e.amiodarone)orneed formedicationchanges.Inaddition,patientswithcardiovascular diseasesshouldbetreated,wheneverpossible,withRbv-free regi-mens,duetothepotentialriskofsideeffectsresultingfromanemia development.
DAA-basedtreatmentoptionsfor HCV patientswithchronic kidneydisease(CKD)arestillrestricted,asadministrationof SOF-basedregimensisnotrecommendedinpatientswithaglomerular filtration rate (eGFR) below 30mL/min. This recommendation resultsfrompharmacokineticdatashowingaccumulationofSOF metabolite GS-331007inpatientswithimpaired renalfunction [56]. While clinical relevance ofthe increasedexposure to GS-331007isstilldebated,manyreal-lifeexperienceshavereported SOF-basedtherapyofHCVpatientswithGFR<30mL/minwith opti-malefficacy,usingdifferenttreatmentschedules (SOF full-dose 400mg/day,200mg/dayor400mg/threetimesaweek)[57]. How-ever,SOF-basedtreatmentofadvancedCKDpatientscanresultin increasedsideeffects,mainlyanemia,andsomepatientsshowed alsorenal functiondeterioration on-therapy, asreportedin the largeTARGETstudy[58].TheonlyapprovedregimensforCKDstage 4–5(GFR<30mL/min)patientsare3D/2DregimenandGZR/EBR combination,whichareeffectiveonlyingenotype1and4patients andarenotrecommendedindecompensatedcirrhosis.The RUBY-1studyevaluatedtheefficacyandsafetyof3D±Rbvfor12weeks in 20genotype 1 CKDstage 4–5patients:18/20(90%) patients achievedSVRandanemiawastheonlysideeffectingenotype1a patients,whereRbvadministrationwasprescribed[59].The fol-lowingRUBY-2studycompared3Dregimenfor12weekswithor withoutRbvingenotype1aCKDpatients,showingnosignificant differenceintreatmentefficacyaccordingtoRbvuse[60]. Concern-ingGZR/EBRcombination, thephase3 C-SURFERstudyshowed 99%SVRrates in224genotype1patientstreatedfor12weeks, withoptimalsafetyprofileasaconsequenceoftheRbv-free regi-men[61].Inaddition,GZR/EBRdisplaysreducedDDIscomparedto 3D/2Dregimens,duetopresenceofsecond-generationDAA com-pounds.Genotype2or3patientswithadvancedCKDhavenow lim-itedtreatmentoptionsexceptfromoff-labeluseofSOF-based reg-imens,howeverthepan-genotypicsecondgenerationNS3+NS5A GLE/PIBcombination,whichisnotrenallyexcreted,isexpectedto provideefficienttreatmentoptions:indeedtheEXPEDITION-4trial reported98%SVRin104genotype1–6CKDpatients[13].
6.8. Statements
• TreatmentchoiceshouldconsiderbaselinefactorsincludingHCV genotype,viralload(inselectedcases),liverfibrosisstageand previoustreatment experience,drug-to-drug interactions and patientco-morbidities.
Table1
Baselinedemographicandvirologicalcharacteristicsoftheincludedpatients.
Characteristics N=23,384 Genotype,n(%) 1a 3060(13%) 1b 13,230(56%) 2 3256(14%) 3 2497(11%) 4 1341(6%) Age,yearsa 59(21–90) Fibrosisstage,n(%) F3 6448(28%) F4 15,388(66%)
Liverstiffness,kPaa 18.3(2–75)
Plateletsx103/mm3a 141(12–990)
Albumin,g/dLa 3.9(1.9–5.6)
Bilirubin,mg/dLa 0.98(0.1–19)
OnwaitinglistforLT,n(%) 103(0.4%) HIVpositive,n(%) 1531(6.5%)
aMedian(range).
• AccurateassessmentofHCVgenotypeandsubtypeingenotype1 byaIIgenerationcommercialassayismandatorybeforestarting aDAA-basedtreatment.HCVsequencingisrecommendedinall rarecaseswheregenotypeorsubtypecannotbedeterminedby thecommercialassays.
• BaselineresistancetestingforRAVbeforefirstcoursewithDAAs haslimitedclinicalutility,unlessifrecommendedbyspecificdrug labels.
7. ReallifeexperiencewithDAAsinItaly
In order to assess the demographic, clinical and virological features of patientstreated withDAAs and theoverall efficacy ofdifferentanti-HCV treatmentsin Italianreal-life practice,we retrospectivelycollectedthedataoffourRegionalHepatitisC Reg-istry(Campania,Lombardia,SiciliaandVeneto)includingallCHC infected patientsover18 years old who consecutivelyreceived DAA-basedtreatment.Overall,betweenJanuary2015andtheend of2016,23,384patientsweretreatedin101treatmentCentres basedontheAIFAcriteria(Table1).Thetreatment’regimenswere chosenbyphysicianaccordingtoEuropean(EASL)andItalian(AISF) liversocieties guidelines.Stageofliverdiseasewasassessedon clinicalground, byliver biopsyor liverstiffness measurements (LSM)consideringasadvancedliverfibrosisLSM≥10kPa. Analy-sisoftreatmentoutcomeisavailablein12,595(54%)patientswho completedtreatmentorfollowup(Table2).OverallSVRratewas
95.6%(12,038/12,595):96%ingenotype1a(1447/1506);96.6%in genotype1b(7229/7482);95%ingenotype2(1558/1642),91.2% ingenotype3(1184/1298)and93%ingenotype4(620/667).The cumulativerateofHCCincirrhoticpatientswithandwithoutSVR was,respectively:2.9%vs15.2%.
ThestrengthofcombiningthedataofthefourlargestItalian registersonDAAsisbasedonthehugenumberofpatientsand thehighnumberofprescribingcenterswithdifferentvolumesof treatedpatientstofullyjustifythedefinitionof“realclinical prac-tice”.Despiteourcollectionmaylacksomeimportantdataatthis time,itconfirmsthatinclinicalpracticetheeffectivenessofDAAs regimensareequaltothosereportedinregistrationtrialswhohave allowedtheapprovalofsometreatmentregimenswithlimiteddata inparticularsubgroupsofpatients.
8. Conclusion
Theavailabilityofhighlyeffectiveandwell-toleratedDAAshas changed theapproach totreating CHC patients. Data fromreal lifereflectandinsomecasesexceedthosereportedinthepivotal trialsandtodayweareabletocureinfectionandhaltliver dis-easeprogressionreducingbothliver-relatedandoverallmortality. Moreoverdataaccumulatedinthelastfewyearsfromreallifewere usefultoimprovepatient’streatmentbothintermofefficacyand safety.
MostoftheclinicalneedsonmanagementofCHCpatientsare resolvedcomparedtolastyear[62].Withnewpan-genotypicDAA combinations,effectiveagainstallviralgenotypesandallstageof liverdiseasehoweverwe canfurtherimprovethemanagement ofourpatientswithpriortreatmentfailureorwithsevererenal impairment,moreoverwithtreatmentsofshorterduration dura-tions.Inthenextfuturewemightfinallyhavethepotentialtotreat theinfectionandnotjustthedisease,withtheaimtoeradicateHCV worldwide.
Conflictofinterest
ViganòM:Consultant/advisor/sponsoredlecturesforBMS,Gilead Sciences,Roche.
PernoCF:Researchgrants,lecturingfees,advisoryboards, scien-tificconsultanciesforAbbvie,GileadSciences,BMS,JanssenCilag, VIIV,Roche,AbbottDiagnostics.
CraxìA:Researchgrants,lecturing fess,advisoryboards, sci-entific consultancy for Novartis, Abbvie, Gilead Sciences, BMS, Achillion,Tibotech,JanssenCilag,AbbottDiagnostics.
Table2
EffectivenessofthedifferenttreatmentregimensaccordingtoHCVgenotype.
Regimens NumberofpatientswithSVR/numberofpatientswithavailabletreatmentoutcome(%)
Genotype1a Genotype1b Genotype2 Genotype3 Genotype4 SOF/LED±Rbv12weeks 412/432(95.3%) 1173/1209(97%) – – 118/130(90.8%) SOF/LED±Rbv24weeks 324/331(97.9%) 1515/1547(98%) – 109/116(93.9%)
SOF+SIM12weeks 58/60(96.7%) 260/279(93.2%) – – –
SOF+SIM+Rbv12weeks 258/280(92.1%) 1425/1519(93.8%) – – 146/162(90.1%)
DCV+SOF12weeks – – 199/202(98.5%) 45/50(90%) – DCV+SOF24weeks 26/28(92.8%) 123/126(97.6%) – 122/130(93.8%) 6/6(100%) DCV+SOF+Rbv12weeks 28/28(100%) 106/106(100%) – 63/65(96.9%) 12/12(100%) DCV+SOF+Rbv24weeks 74/74(100%) 228/230(99.1%) – 656/671(97.8%) 16/16(100%) 3D+Rbv12weeks 101/104(97.1%) 991/1011(98%) – – 3D+Rbv24weeks 166/169(98.2%) 1360/1383(98.3%) – – 2D+Rbv12weeks – – – – 80/82(97.5%) 2D+Rbv24weeks – – – – 122/124(98.4%) SOF+Rbv12weeks – – 601/633(94.9%) – – SOF+Rbv24weeks – 48/72(66.7%) 758/807(93.9%) 264/345(76.5%) 11/19(57.9%) SOF/PegIFN/Rbv12weeks – – 34/37(91.9%) –
SOF:sofosbuvir,LED:ledipasvir,Rbv:ribavirin,SIM:simeprevir,DCV:daclatasvir,3D:ombitasvir/paritaprevir/ritonaviranddasabuvir,2D:ombitasvir/paritaprevir/ritonavir, PegIFN:pegylatedinterferon.
Aghemo A: Advisory Boards: BMS, MSD, Gilead Sciences,
Janssen,AbbVie;Speaker:BMS,MSD,GileadSciences,Janssen,
Abb-Vie:ResearchGrant:GileadSciences.
AlbertiA:Advisorboardespeakerfee:GileadSciences,Abbivie,
BMSMSD,Janssen;Researchfounding:GileadSciences,Janssen,
Abvvie,MSD.
AndreoneP:Research grantsfromGileadSciences, MSDand
Roche;advisorforJanssen,MSD,Roche,AbbVie,BMS,Gilead
Sci-ences;consultantforBMS,MSD,AbbVie.
AndreoniM:Attendingsymposia,speaking,organizing
educa-tional activities,consultancyor advisoryboard membership,or
grant researchsupport fromMS GileadSciences, BMS,Janssen,
ViivHealthcare,MSD,AbbVie,AstraZeneca,BoheringerIngelheim,
Pfizer.
BonoraS: Recipient of travel grants, advisory board fees or
speakerfeesfromMSD,Viiv,Janssen,BMS,AbbvieandGilead
Sci-ences.
BrunettoMR:Speakers’bureau:BMS,GileadSciences,Janssen,
Roche;advisoryboard:GileadSciences,Janssen,Abbvie,MSD.
Bruno R: Advisory board and speaker Abbvie, BMS, Gilead,
Janssen,MSD.
BrunoS:Advisoryboard MSD,AbbVie,speakerbureauMSD,
speakerAbbVie,BMS,GileadSciences,Janssen,MSD.
CalvarusoV:Travelgrant,speaking,teachingandparticipation
toadvisoryboardfor:AbbVie,BMS,GileadSciencesandIntercept.
Grantandresearchsupport:MSD.
CaporasoN:SpeakingandteachingAbbvie,BMS,GileadScience,
Janssen,MSD.AdvisorycommitteesofAbbvie,BMS,GileadScience,
Janssen,MSD.
Ceccherini-SilbersteinF:Attendingsymposia,speaking,
orga-nizing educational activities, consultancy or advisory board
membership,orgrantresearchsupportfromAbbVie,Abbott
Molec-ular,BMS,GileadSciences,Janssen-Cilag,MSD,RocheDiagnostics
andViiVHealthcare.
CentoV:Advisoryboardsand/orlecturerforAbbvie,BMS,MSD,
Janssen-Cilag.
CiancioA:SpeakerbureauforMSD;BMS,GileadSciences,
Abb-vie.
ColombattoP:AdvisoryboardAbbVie;speakerbureau:Janssen
eBMS.
DegasperiE:None.
DiMarcoV:Speakingandadvisorfor:AbbVie,BMS,Gilead,MSD,
Roche.Grant andresearchsupport:Abbvie,Bayer, BMS,Gilead,
MSD,Roche.
DiPerriG:Speakerandadvisorfor:Abbvie,BMS,MSD,Gilead
Sciences,Janssen,ViiV,Pfizer,Novartis,Aventis.
D’offizi G: Speaking, teaching and participation to advisory
boardfor:Gilead,BMS,MSD.
FagiuoliS:Speakerbureau:GileadSciences,BMS,MSD,Abbvie,
Janssen,Novartis,Kedrion,Biotest,Bayer.
FerrariC:ResearchgrantsfromGileadSciences,Roche,Janssen;
servedasadvisor/consultantforGileadSciences,MSD,Abbvie,BMS
andArrowhead.
GaetaGB:SpeakerorAdvisorfor:MSD,GileadSciences,BMS,
Abbvie,Janssen,Roche.
PellicelliA:None.
PettaS:Consultant/Advisor/SponsoredlecturesforAbbvie,BMS,
GileadSciences,Janssen-Cilag,MSD.
PiovesanS:None.
PuotiM:Advisoryboardsand/orlecturerinowneventsand/or
researchgrantsfromAbbvie,Janssen,Gilead, BMS,MSD,Roche,
ViiV.
Raimondo G: Grant/researchsupport: GileadSciences, MSD;
Consultant/Advisor:Abbvie, BMS,GileadSciences, MSD, Roche;
Sponsored lectures: Abbvie, Bayer, BMS, Gilead Sciences, MSD,
Roche.
RussoFP:ResearchgrantfromAbbvieandBMS,lecturingfees,
advisoryboardsforAbbvie,GileadSciences,Biotest,BMS,Janssen
Cilag.
TalianiG:Travelgrant,speaking,teachingandparticipationto
advisoryboardfor:AbbVie,BMS,GileadSciences,MSD,Janssen,
Roche.
TramaU:None.
VillaE:Advisorycommitteesor reviewpanels:Abbvie,BMS,
GileadSciences,GlaxoSmithKline,MSD,Roche;speakingand
teach-ing:Abbvie,GlaxoSmithKline,Novartis.
Zignego AL: Speakerbureau for BMS, GileadSciences, MSD,
Janssen.
AppendixA
aDivisionofGastroenterologyandHepatology,FondazioneIRCCS
Ca’ Granda Ospedale Maggiore Policlinico, University of Milan,
Milan,Italy
bDepartmentofMolecularMedicine,UniversityofPadua,Padua,
Italy
cDepartmentofMedicalandSurgicalSciences,BolognaUniversity,
Bologna,Italy
dDepartmentofInfectiousDiseases,UniversityofRomeTor
Ver-gata,Rome,Italy
eUnit of Infectious Diseases, Department of Medical Sciences,
UniversityofTurin,Turin,Italy
fHepatologyUnit,UniversityHospitalofPisa,Pisa,Italy
gUnitofInfectiousandTropicalDiseases,UniversityofPavia,Pavia,
Italy
hDepartmentofInternalMedicine,HumanitasUniversityMedicine,
Rozzano,Italy
iDepartmentofGastroenterology,DiBiMIS,UniversityofPalermo,
Palermo,Italy
jDepartmentofClinical MedicineandSurgery,Gastroenterology
Unit,UniversityofNaples ¨FedericoII¨,Naples,Italy
kVirologyUnit,DepartmentofExperimentalMedicineandSurgery,
“TorVergata”UniversityofRome,Rome,Italy
lDepartment of Gastroenterology and Hepatology, Città della
Salute edellaScienzaHospitaland Department ofMedical
Sci-ences,UniversityofTurin,Turin,Italy
mUnitofInfectiousDiseasesandHepatology,INMI“Lazzaro
Spal-lanzani”Rome,Italy
nDepartment of Gastroenterology, Hepatology and Liver
Trans-plantation,PapaGiovanniXXIIIHospital,Bergamo,Italy
oUnitofInfectiousDiseasesandHepatology,AOUdiParma,Parma,
Italy
pSectionofInfectiousDiseases,DepartmentofInternalMedicine,
SecondUniversityofNaples,Naples,Italy
qLiverUnit,SanCamilloForlaniniHospital,Rome,Italy
rDivisionofInfectiousDiseases,AOOspedaleNiguardaCa’Granda,
Milan,Italy
sDivision of Clinical and Molecular Hepatology, Department of
InternalMedicine,UniversityHospitalofMessina,Messina,Italy
tSection of Gastroenterology/Multivisceral Transplant Unit,
Department of Surgery, Oncology and Gastroenterology, Padua
UniversityHospital,Padua,Italy
uInfectious and Tropical Diseases Unit, Department of Clinical
Medicine,SapienzaUniversityofRome,Rome,Italy
vUOD08(PoliticadelFarmaco)dellaRegioneCampania,Italy
wDivisionofGastroenterology,AOUPoliclinicodiModena,
Univer-sityofModenaandReggioEmilia,Modena,Italy
xCenterforSystemicManifestationsofHepatitisViruses(MASVE),
DepartmentofExperimentalandClinicalMedicine,Universityof
References
[1]Webster DP, Klenerman P, Dusheiko GM. Hepatitis C. The Lancet 2015;385:1124–35.
[2]GBD2013MortalityandCausesofDeathCollaborators.Global,regional,and nationalage-sexspecificall-causeandcause-specificmortalityfor240causes ofdeath,1990–2013:asystematicanalysisfortheGlobalBurdenofDisease Study2013.TheLancet2015;385:117–71.
[3]AlterMJ.EpidemiologyofhepatitisCvirusinfection.WorldJournalof Gas-troenterology2007;13:2436–41.
[4]MessinaJP,HumphreysI,FlaxmanA,etal.Globaldistributionandprevalence ofhepatitisCvirusgenotypes.Hepatology2015;61:77–87.
[5]vanderMeerAJ,VeldtBJ,FeldJJ,etal.Associationbetweensustainedvirological responseandall-causemortalityamongpatientswithchronichepatitisCand advancedhepaticfibrosis.JAMA2012;308:2584–93.
[6]DeterdingK,HoenerzuSiederdissenC,PortK,etal.Improvementofliver func-tionparametersinadvancedHCVassociatedlivercirrhosisbyIFN-freeantiviral therapies.AlimentaryPharmacologyTherapeutics2015;42:889–901.
[7]JacobsonIM,AsselahT,NahassR,etal.Arandomizedphase3trialof Sofosbu-vir/Velpatasvir/Voxilaprevirfor8weekscomparedtoSofosbuvir/Velpatasvir for12weeksinDAA-naïvegenotype1–6HCVinfectedpatients:thePOLARIS-2 study.Hepatology2016;64(Suppl.S1)[AbstractLB12].
[8]ZeuzemS,FlammSL,TongM,etal.Arandomized,controlled,phase3trialof Sofosbuvir/Velpatasvir/VoxilaprevirorSofosbuvir/Velpatasvirfor12weeksin direct-actingantiviral-experiencedpatientswithgenotype1–6HCVinfection: thePOLARIS-4study.Hepatology2016;64(Suppl.S1)[Abstract109].
[9]ZeuzemS,FeldJ,WangS,etal.ENDURANCE-1:aphase3evaluationofthe effi-cacyandsafetyof8-versus12-weektreatmentwithGlecaprevir/Pibrentasvir (formerlyABT-493/ABT-530)inHCVgenotype1infectedpatientswithor with-outHIV-1co-infectionandwithoutcirrhosis.Hepatology2016;64(Suppl.S1) [Abstract253].
[10]AsselahT,Hezode,ZadeikisN,etal.ENDURANCE-4:efficacyandsafetyof Glecaprevir/Pibrentasvir(FormerlyABT-493/ABT-530)treatmentinpatients withchronicHCVgenotype4,5,or6infection.Hepatology2016;64(Suppl.S1) [Abstract114].
[11]KowdleyKV,ColomboM,ZadeikisN,etal.ENDURANCE-2:safetyandefficacy ofGlecaprevir/PibrentasvirinhepatitisCvirusgenotype2-infectedpatients withoutcirrhosis:arandomized,double-blind,placebo-controlledstudy. Hep-atology2016;(Suppl.S1):64[Abstract73].
[12]WylesD,PoordadF,WangS,etal.SURVEYOR-II,part3:efficacyandsafety ofGlecaprevir/Pibrentasvir(ABT-493/ABT-530)inpatientswithhepatitisC virusgenotype3infectionwithpriortreatmentexperienceand/orcirrhosis. Hepatology2016;64(Suppl.S1)[Abstract113].
[13]Gane E,LawitzE,PugatchD, etal.EXPEDITION-4:efficacyand safetyof Glecaprevir/Pibrentasvir(ABT-493/ABT-530)inpatientswithrenal impair-ment and chronic hepatitis C virus genotype 1–6 infection. Hepatology 2016;64(Suppl.S1)[AbstractLB11].
[14]LawitzE,YoshidaEM,ButiM,etal.Safetyandefficacyofthefixed-dose combi-nationregimenofMK-3682/Grazoprevir/MK-8408(Ruzasvir)withorwithout ribavirininnon-cirrhoticorcirrhoticpatientswithchronicHCVGT1,2or3 infection(PartBofC-CREST-1&-2).Hepatology2016;64(Suppl.S1)[Abstract 110].
[15]WylesD,WedemeyerH,ReddyKR,etal.Safetyandefficacyofthefixed-dose combinationregimen ofMK-3682/Grazoprevir/MK-8408(Ruzasvir) in cir-rhoticornon-cirrhoticpatientswithchronicHCVGT1infectionwhopreviously failedadirect-actingantiviralregimen(C-SURGE).Hepatology2016;64(Suppl. S1)[Abstract193].
[16]EASL.RecommendationsontreatmentofhepatitisC.JournalofHepatology 2017;66:153–94.
[17]SulkowskiMS,GardinerDF,Rodriguez-TorresM,etal.Daclatasvirplus sofos-buvirforpreviouslytreatedoruntreatedchronicHCVinfection.NewEngland JournalofMedicine2014;370:211–21.
[18]PoordadF,SchiffER,VierlingJM,etal.Daclatasvirwithsofosbuvirandribavirin forhepatitisCvirusinfectionwithadvancedcirrhosisorpost-liver transplan-tationrecurrence.Hepatology2016;63:1493–505.
[19]ZhouN,HanZ,Hartman-NeumannS,etal.CharacterizationofNS5A polymor-phismsandtheirimpactonresponseratesinpatientswithHCVgenotype2 treatedwithdaclatasvir-basedregimens.JournalofAntimicrobial Chemother-apy2016;71:3495–505.
[20]MangiaA,ArleoA,CopettiM,etal.Thecombinationofdaclatasvirand sofos-buvir forcuringgenotype2patientswhocannot tolerateribavirin.Liver International2016;36:971–6.
[21]CacciolaI,PettaS,DistefanoM,etal.Efficacyoforaldirectactingantiviralsfor treatmentofadvancedchronichepatitisorcompensatedcirrhosisdueto hep-atitisCvirusinfection:thereal-lifeexperienceoftheSicilyregistry.Digestive andLiverDisease2017;49S:e6[OC-11].
[22]FeldJJ,JacobsonIM,HézodeC, etal. SofosbuvirandVelpatasvirforHCV genotype 1, 2, 4, 5, and 6 infection. New England Journal of Medicine 2015;373:2599–607.
[23]FosterGR,AfdhalN,RobertsSK,etal.SofosbuvirandVelpatasvirforHCV geno-type2and3infection.NewEnglandJournalofMedicine2015;373:2608–17.
[24]TackeF,GüntherR,BuggischP,etal.TreatmentofHCVgenotype2with sofos-buvirandribavirinresultsinlowersustainedvirologicalresponseratesinreal lifethanexpectedfromclinicaltrials.LiverInternational2017;37:205–11.
[25]WelzelTM,NelsonDR,MorelliG,etal.Effectivenessandsafetyofsofosbuvir plusribavirinforthetreatmentofHCVgenotype2infection:resultsofthe real-world,clinicalpracticeHCV-TARGETstudy.Gut2016[Epubaheadofprint].
[26]CurryMP,O’LearyJG,BzowejN,etal.SofosbuvirandVelpatasvirforHCV inpatientswithdecompensatedcirrhosis.NewEnglandJournalofMedicine 2015;373:2618–28.
[27]SusserS,DietzJ,BarakM,etal.Prevalenceandclinicalimportanceofhepatitis Cvirusgenotype2K/1Bchimeras.JournalofHepatology2016;64:S136.
[28]SusserS,DietzJ,VermehrenJ,etal.EuropeanRavsdatabase:frequencyand characteristicsofRavsintreatment-naïveandDAA-experiencedpatients. Jour-nalofHepatology2016;64:S139.
[29]AASLD/IDSAHCVGuidancePanel. HepatitisCGuidance:AASLD-IDSA rec-ommendationsfortesting,managing,andtreatingHepatitisC[http://www. hcvguidelines.org].
[30]NelsonDR,CooperJN,LalezariJP,etal.All-oral 12-weektreatmentwith daclatasvirplussofosbuvirinpatientswithhepatitisCvirusgenotype3 infec-tion:ALLY-3phaseIIIstudy.Hepatology2015;61:1127–35.
[31]McPheeF,HernandezD,ZhouN,etal.Next-generationsequencinganalysis ofNS5AandNS5Bminorresistance-associatedvariantsinpatientswithHCV genotype3infectionwhofailedtreatmentwithDaclatasvirplusSofosbuvir. JournalofHepatology2016;64:S614–5.
[32]LeroyV,AngusP,BronowickiJP,etal.Daclatasvir,sofosbuvir,andribavirinfor hepatitisCvirusgenotype3andadvancedliverdisease:arandomizedphase IIIstudy(ALLY-3+).Hepatology2016;63:1430–41.
[33]PasuloL,AghemoA,QuirinoT,etal.Genotype3infectioninDAAera:reports ofareallifeNorthernItalyNetworkforviralhepatitisafter2yearsbythestart. DigestiveandLiverDisease2017;49S:e68[F-47].
[34]PellicelliA,MessinaV,TarquiniP,etal.Daclatasvir/sofosbuvirandribavirin 800mgflatdoseishighlyefficacyandsafeingenotype3compensatedand decompensatedcirrhoticpatients:theCLEOexperience.DigestiveandLiver Disease2017;49S:e64[F-39].
[35]HézodeC,LebrayP,DeLedinghenV,etal.Daclatasvirplussofosbuvir,with orwithoutribavirin,forhepatitisCvirusgenotype3inaFrenchEarlyAccess Programme.LiverInternational2017[Epubaheadofprint].
[36]FosterGR,ThompsonAJ,RuanePJ,etal.Arandomizedphase3trialof Sofos-buvir/Velpatasvir/Voxilaprevirfor8weeksandSofosbuvir/Velpatasvirfor12 weeksforpatientswithgenotype3HCVinfectionandcirrhosis:thePOLARIS-3 study.Hepatology2016;64(Suppl.S1)[Abstract258].
[37]WelzelTM,PetersenJ,HerzerK,etal.Daclatasvirplussofosbuvir,withor with-outribavirin,achievedhighsustainedvirologicalresponseratesinpatients withHCVinfectionandadvancedliverdiseaseinareal-worldcohort.Gut 2016;65:1861–70.
[38]MuirAJ,StrasserS,WangS,etal.HighSvrrateswithABT-493+ABT-530 co-administeredfor8weeksinnon-cirrhoticpatientswithHCVgenotype3 infection.JournalofHepatology2016;64:S186.
[39]FosterGR,GaneE,AsatryanA,etal.Endurance-3:aphase3,randomized, open-label,active-controlledstudytocompareefficacyandsafetyof ABT-493/ABT-530toSofosbuvirco-administeredwithDaclatasvirinadultswith HCVgenotype3infection.JournalofHepatology2016;64:S292.
[40]BourlièreM,GordonSC,RamjiA,etal.Sofosbuvir/Velpatasvir/Voxilaprevirfor 12weeksasasalvageregimeninNAinhibitor-experiencedpatientswith geno-type1–6infection:thephase3POLARIS-1study.Hepatology2016;64(Suppl. S1)[Abstract194].
[41]AragriM,DiMaioVC,DiPaoloD,etal.Intheeraofnewdirectacting antivi-ralagentsHCVsequencingallowsthemostaccuratesubtypeandgenotype assignment.JournalofHepatology2016;64:S419–20.
[42]DiMaioVC,CentoV,LenciI,etal.MulticlassHCVresistanceto interferon-freedirectactingantiviralsregimensinreallifefailuresadvocatesfortailored second-linetherapies.DigestiveandLiverDisease2017;49S:e49–50[F-14].
[43]WylesD,PockrosP,MorelliG,etal.Ledipasvir-sofosbuvirplusribavirinfor patientswithgenotype1hepatitisCviruspreviouslytreatedinclinicaltrials ofsofosbuvirregimens.Hepatology2015;61:1793–7.
[44]SullivanJC,DeMeyerS,BartelsDJ,etal.Evolutionoftreatment-emergent resis-tantvariantsintelaprevirphase3clinicaltrials.ClinicalInfectiousDiseases 2013;57:221–9.
[45]AfdhalN,ReddyKR,NelsonDR,etal.Ledipasvirandsofosbuvirfor previ-ouslytreatedHCVgenotype1infection.NewEnglandJournalofMedicine 2014;370:1483–93.
[46]Dvory-SobolH,WylesD,OuyangW,etal.Long-termpersistenceofHCVNS5A variantsaftertreatmentwithNS5Ainhibitorledipasvir.JournalofHepatology 2015;62:S221.
[47]LahserF,GallowayA,HwangP,etal.Interimanalysisofa3-yearfollow-up studyofNAandNS3resistance-associatedvariants(RAVs)aftertreatmentwith Grazoprevir-containingregimensinpatientswithchronichepatitisCvirus (HCV)infection.Hepatology2016;64(Suppl.S1)[Abstract61].
[48]WylesD,Dvory-SobolH,SvarovskaiaES,etal.Post-treatmentresistance analy-sisofhepatitisCvirusfromphaseIIandIIIclinicaltrialsofledipasvir/sofosbuvir. JournalofHepatology2016:30699–707[Epubaheadofprint].
[49]Poordad F, Gordon SC,Asatryan A,et al. High efficacy of ABT-493 and ABT-530inHCVgenotype1-infectedpatientswhohavefaileddirect-acting antiviral-containingregimens:theMAGELLAN-1study.JournalofHepatology 2016;64:S160–1.
[50]CeccheriniSilbersteinF,DiMaioVC,AragriM,etal.HepatitisCvirusgene sequencingasatoolforprecisegenotypingintheeraofnewdirectantiviral agents.Hepatology2016;63:1058–9.
[51]KowdleyKV,GordonSC,ReddyKR,etal.Ledipasvirandsofosbuvirfor8or 12weeksforchronicHCVwithoutcirrhosis.NewEnglandJournalofMedicine 2014;370:1879–88.
[52]ZeuzemS,GhalibR,ReddyKR,etal.Grazoprevir-Elbasvircombinationtherapy fortreatment-naivecirrhoticandnoncirrhoticpatientswithchronichepatitis Cvirusgenotype1,4,or6infection:arandomizedtrial.AnnalsofInternal Medicine2015;163:1–13.
[53]KwoP,GaneE,PengCY,etal.Efficacyandsafetyofgrazoprevir/elbasvirplus orminusRBVfor12weeksinpatientswithHCVG1orG4infectionwho previ-ouslyfailedpeginterferon/RBV:C-EDGETreatment-Experiencedtrial.Journal ofHepatology2015;62:S674–5.
[54]ZeuzemS,MizokamiM,PlankoS,etal.NS5Aresistance-associated substitu-tionsinpatientswithgenotype1hepatitisCvirus:prevalenceandeffecton treatmentoutcome.JournalofHepatology2017[Epubaheadofprint].
[55]SarrazinC,Dvory-SobolH,SvarovskaiaES,etal.Prevalenceof resistance-associatedsubstitutionsinHCVNS5A,NS5B,orNS3andoutcomesoftreatment withLedipasvirandSofosbuvir.Gastroenterology2016;151:501–12.
[56]DesnoyerA,PospaiD,LêMP,etal.Pharmacokinetics,safetyandefficacyofa fulldosesofosbuvir-basedregimengivendailyinhemodialysispatientswith chronichepatitisC.JournalofHepatology2016;65:40–7.
[57]De Nicola S,Aghemo A. Thequest for safe and effective treatmentsof chronichepatitisCinpatientswithkidneyimpairment.LiverInternational 2016;36:791–3.
[58]SaxenaV,KoraishyFM,SiseME, etal.Safetyand efficacyof sofosbuvir-containingregimensinhepatitis C-infected patientswith impairedrenal function.LiverInternational2016;36:807–16.
[59]PockrosPJ,ReddyKR,MantryPS,etal.Efficacyofdirect-actingantiviral combi-nationforpatientswithhepatitisCvirusgenotype1infectionandsevererenal impairmentorend-stagerenaldisease.Gastroenterology2016;150:1590–8.
[60]GaneEJ,SolàR,CohenE,etal.RUBY-II:efficacyandsafetyofaribavirin-free Ombitasvir/Paritaprevir/Ritonavir±Dasabuvirregimeninpatientswithsevere renalimpairmentorend-stagerenaldiseaseandHCVgenotypes1aor4 infec-tion.Hepatology2016;64(Suppl.S1)[Abstract935].
[61]RothD,NelsonDR,BruchfeldA,etal.Grazoprevirpluselbasvirin treatment-naiveandtreatment-experiencedpatientswithhepatitisCvirusgenotype1 infectionandstage4–5chronickidneydisease(theC-SURFERstudy):a com-binationphase3study.TheLancet2015;386:1537–45.
[62]CraxiA,PernoCF,ViganòM,etal.FromcurrentstatustooptimizationofHCV treatment:recommendationsfromanexpertpanel.DigestiveandLiverDisease 2016;48:995–1005.
